The role of adenosine A2A receptors in regeneration of afferent synapses in the cochlea after excitotoxic injury

Abstract

Noise-induced hearing loss is a common form of sensorineural hearing loss caused by excessive noise exposure. This often results in the degeneration of the neural and sensory structures within the inner ear. The damage caused by excessive noise was thought to primarily affect the survival of sensory hair cells, followed by secondary degeneration of auditory neurons. However, recent studies have indicated asymptomatic neural degeneration that precedes hair cell loss and auditory threshold changes. This observation was termed hidden hearing loss, which was characterised by hearing impairment independent of threshold changes. Evidence from previous research revealed that changes to the adenosine receptor activity in the inner ear influenced the outcome of cochlear injury, with emphasis on the opposing roles of A1 and A2A receptors. Therefore, the aim of the current study is to determine whether inhibition of the A2A receptors can protect the developing rat cochlea from excitotoxic injury. To address this research question, an excitotoxicity model was used in organotypic tissue culture to simulate excessive glutamatergic stimulation and cause cochlear injury similar to that from excessive noise exposure. Cochlear explants obtained from post-natal day 6 Wistar rats were cultured and subjected to NMDA/kainate (NK) excitotoxic injury followed by treatment with A2A receptor antagonist istradefylline. The outcome measures for the current project included quantification of the density of afferent processes from spiral ganglion neurons projecting to the inner hair cells, as well as the number of paired synapses at the inner hair cell - auditory nerve synapse. The excitotoxic injury model was characterised by a reduction in cochlear afferents immediately after NK administration and the loss of ribbon synapses in the presence of intact sensory hair cells. The injury reached the peak at 18 hours post-NK treatment, followed by the onset of spontaneous regeneration at 24 hours. The treatment with istradefylline effectively reduced the loss of afferent fibres and synapses 18 hours after excitotoxic injury with full preservation of sensory tissues. These studies suggest that inhibition of A2A receptors activity promotes cochlear recovery from excitotoxic injury, which has implications for the therapeutic management of noise-induced hearing loss.